RxPG News : Bipolar Disorder

Genes behind bipolar disorder mapped by scientists

Sun, 23 Nov 2008 11:44:57 PST

( from http://www.rxpgnews.com ) New York, Nov 22 - In a first, scientists have comprehensively mapped the genes believed to cause bipolar disorder.

Indiana University neuroscientists combined data from the latest gene hunting studies for bipolar disorder with information from their own studies to zero in on the best candidate genes for the illness.

Their findings, reported in the latest issue of the American Journal of Medical Genetics, describe how researchers analysed how these genes work together to create a comprehensive biological model of bipolar disorder.

'Based on our work, we now project that there will be hundreds of genes -- possibly as much as 10 percent of the human genome -- involved in this illness,' said Alexander B. Niculescu, who led the team, in a press release.

'Not all genetic mutations will occur in every individual with bipolar disorder. Different individuals will have different combinations of genetic mutations. This genetic complexity is most likely what made past attempts to identify genes for the disorder through genetic-only studies so difficult and inconsistent.'

Until now there have been few statistically significant findings in searches of the human genome as it applies to bipolar disorder, he said.

'By integrating the findings of multiple studies, we were able to sort through, identify genes that were most likely to be involved in bipolar disorder, and achieve this major breakthrough in our understanding of the illness,' Niculescu said.

Bipolar disorder, sometimes called manic depression, affects millions worldwide and people who suffer from it can experience mild or dramatic mood swings, shifts in energy and a diminished capacity to function.

The findings of the study hold out the hope that, having assessed individual gene combinations, individuals likely to suffer from bipolar disorder can be identified even before the illness manifests itself.

This could result in preventive measures like lifestyle changes, counselling and low-dose medications.

First genome-wide study revealed genetic roots of bipolar illness

Wed, 23 May 2007 04:00:00 PST

( from http://www.rxpgnews.com ) The likelihood of developing bipolar disorder depends in part on the combined, small effects of variations in many different genes in the brain, none of which is powerful enough to cause the disease by itself, a new study shows. However, targeting the enzyme produced by one of these genes could lead to development of new, more effective medications. The research was conducted by scientists at the National Institutes of Health's National Institute of Mental Health (NIMH), with others from the Universities of Heidelberg and Bonn and a number of U.S. facilities collaborating in a major project called the NIMH Genetics Initiative.

The study is the first to scan virtually all of the variations in human genes to find those associated with bipolar disorder. Results were published online May 8 in Molecular Psychiatry by Amber E. Baum, PhD, lead researcher Francis J. McMahon, MD, and colleagues.

This is an example of how advances in genetics research feed into practical applications. This research would not have been possible a very few years ago. We now have a new molecular target scientists can investigate in their search for better medications for bipolar disorder, said NIH Director Elias A. Zerhouni, MD.

About 5.7 million American adults have bipolar disorder, which also is called manic-depressive illness. Symptoms include extremes in mood, from pronounced over-excitement and elation, often coupled with severe irritability, to depression. Children also may have the condition, usually in a more severe form than adults.

We're beginning to get a foothold on the genetics of this complex brain disorder, said NIMH Director Thomas R. Insel, MD.

Most people occasionally have mood swings, but the shifts that occur in bipolar disorder, and the changes in behavior and energy level that accompany them, are sometimes disabling. Lithium and the other mood-stabilizing medications used to treat the condition help many patients.

But some people do not respond to these medications, and clinicians need more options so that they can tailor treatments to each patient. People inherit different gene variations, which may influence whether or not they respond to a given medication. Identifying and targeting these variations could help scientists develop additional medication options that take these differences into account.

One of the genes the researchers correlated with the disorder, DGKH, is active in a biochemical pathway through which lithium is thought to exert its therapeutic effects. The gene produces an enzyme (diacylglycerol kinase eta) that functions at a point closer to the root of the lithium-sensitive pathway than does the protein that lithium is thought to target. Scientists can now try to develop more effective medications by focusing on new compounds that act on the DGKH enzyme or regulate how much of the enzyme is produced. The DGKH gene is on chromosome 13.

Several other genes detected in the study produce proteins involved in this and other biochemical pathways thought to play a role in bipolar disorder. Understanding the effects that variations of these genes have on brain-cell function could lead to explanations of how they contribute to the condition and how it might be better prevented or treated.

Treatments that target just a few of these genes or the proteins they make could yield substantial benefits for patients. Lithium is still the primary treatment for bipolar disorder, but DGKH is a promising target for new treatments that might be more effective and better tolerated, McMahon said.

The finding was enabled by recent genetics technology that allows researchers to scan, in a single experiment, thousands of genes for variations. Everyone has the same genes, but variations in them influence whether or not a person gets a specific disease. In this study, researchers compared variations found in the scans of 413 adults who had bipolar disorder with variations found in the scans of 563 healthy adults.

By pooling the genetic material of the adults with bipolar disorder, the U.S. researchers were able to scan the entire group at a small fraction of the cost of scanning each person's material individually. The genetic material of the healthy group was pooled and scanned separately, again at a fraction of the cost of individual scans. The researchers then zeroed in on the gene variations that occurred more often in the people with bipolar disorder and examined them individually.

An important issue in genetics research is that findings correlating specific genes with specific diseases in one population may not apply to other populations. This study addressed that issue by focusing on US participants of European ancestry, then repeating the study in a large group of patients in Germany. Similar outcomes were found in both populations, strengthening the validity of the results. A subsequent study is examining whether the results apply to other populations, and will look for common variations among them.

The researchers will soon make the results of their scans available, on a website, to other scientists who are pursuing this line of research.

Diagnosis of Major Depression Might Mask Bipolar illness

Wed, 09 May 2007 08:32:37 PST

( from http://www.rxpgnews.com ) Approximately 4.4 percent of U.S. adults may have some form of bipolar disorder during some point in their lifetime, including about 2.4 percent with a "sub-threshold" condition, according to an article in the May issue of Archives of General Psychiatry, one of the JAMA/Archives journals.

Individuals with bipolar disorder tend to fluctuate between periods of maniaâan inappropriately elevated mood, characterized by impulsive behavior and an increased activity levelâand periods of depression. They are at increased risk of suicide and other medical problems, such as cardiovascular disease, according to background information in the article. Previously, researchers estimated that about 1 percent of adults had bipolar disorder. But evidence indicates that current diagnostic criteria may be too narrow to effectively detect bipolar disorder in the general population, and that a broader definition of bipolar spectrum disorder would identify many more individuals with bipolar symptoms, the authors note.

"The present results reinforce the argument of other researchers that clinically significant sub-threshold bipolar disorder is as least as common as threshold bipolar disorder," the authors write. "Although most individuals with bipolar disorder receive treatment owing to co-morbid disorders, the lack of recognition of their underlying bipolarity leads to only a few receiving appropriate treatment." The findings suggest that a substantial proportion of those diagnosed with major depression may actually have a form of bipolar disorder.

More individuals with other psychiatric disorders should also be screened for bipolar disorder, the authors conclude. "Additional research is needed to resolve uncertainty regarding the most appropriate threshold and boundary distinctions for bipolar disorder. This uncertainty remains a major impediment to advancing the understanding of the bipolar disorder spectrum in the population."

Intensive psychotherapy more effective than brief therapy for treating bipolar depression

Tue, 03 Apr 2007 03:09:24 PST

( from http://www.rxpgnews.com ) Patients taking medications to treat bipolar disorder are more likely to get well faster and stay well if they receive intensive psychotherapy, according to results from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), funded by the National Institutes of Healthâs (NIH) National Institute of Mental Health (NIMH). The results are published in the April 2007 issue of the Archives of General Psychiatry.

Bipolar disorder is a debilitating illness marked by severe mood swings between depression and mania that affects 2.6 percent of Americans in any given year. "We know that medication is an important component in the treatment of bipolar illness. These new results suggest that adding specific, targeted psychotherapy to medication may help give patients a better shot at lasting recovery," said NIH Director Dr. Elias A. Zerhouni.

"STEP-BD is helping us identify the best toolsâboth medications and psychosocial treatmentsâthat patients and their clinicians can use to battle the symptoms of this illness," said NIMH Director Thomas R. Insel, M.D.

Psychotherapy is routinely employed as a means to treat bipolar illness in conjunction with medication, but the extent to which psychotherapy is effective has been unclear. In addition, most psychotherapeutic studies have been limited to a single site and compared only one type of treatment to routine care. Thus, in addition to examining the role of medication, STEP-BD set out to compare several types of psychotherapy and pinpoint the most effective treatments and treatment combinations.

With 293 participants, David Miklowitz, Ph.D., of the University of Colorado and colleagues set out to test the effectiveness of three types of standardized, intensive, nine-month-long psychotherapy compared to a control group that received a three-session, psychoeducational program called collaborative care. The intensive therapies were:

family-focused therapy, which required the participation and input of patientsâ family members and focused on enhancing family coping, communication and problem-solving;
cognitive behavioral therapy, which focused on helping the patient understand distortions in thinking and activity, and learn new ways of coping with the illness; and
interpersonal and social rhythm therapy, which focused on helping the patient stabilize his or her daily routines and sleep/wake cycles, and solve key relationship problems.

All participants were already taking medication for their bipolar disorder, and most were also enrolled in a STEP-BD medication study reported in the New England Journal of Medicine online on March 28, 2007. The researchers compared patientsâ time to recovery and their stability over one year.

Over the course of the year, 64 percent of those in the intensive psychotherapy groups had become well, compared with 52 percent of those in collaborative care therapy. Patients in intensive psychotherapy also became well an average of 110 days faster than those in collaborative care. In addition, patients who received intensive psychotherapy were one and a half times more likely to be clinically well during any month out of the study year than those who received collaborative care. Discontinuation rates among the groups were similarâ36 percent of those in the intensive programs discontinued and 31 percent of those in collaborative care discontinued. None of the three intensive psychotherapies appeared to be significantly more effective than the others, although rates of recovery were higher among those in family-focused therapy compared to the other groups.

"Intensive psychotherapy, when used as an adjunctive treatment to medication, can significantly enhance a personâs chances for recovering from depression and staying healthy over the long term," said Dr. Miklowitz. "It should be considered a vital part of the effort to treat bipolar illness."

New Treatment Model for Bipolar Disorder Shows Promise

Fri, 11 Aug 2006 20:09:00 PST

( from http://www.rxpgnews.com ) A new care model for bipolar disorder tested in veterans across the nation reduced their manic episodes and improved their quality of life, according to research led by a psychiatrist with the Providence Veterans Affairs Medical Center and Brown Medical School.

The randomized, controlled trial also showed that the model did not add to the treatment costs for bipolar disorder, which affects nearly 6 million American adults a year. Results appear in two reports published in Psychiatric Services, a journal of the American Psychiatric Association.

We applied the same symptom management approaches found in interventions for diabetes and asthma to the treatment of bipolar disorder and found that people with serious mental illness can help take control of their care, said Mark S. Bauer, M.D., staff psychiatrist with the Providence V.A. Medical Center and professor of psychiatry and human behavior at Brown Medical School. This finding should reduce the stigma of helplessness that so often is associated with these disorders, and it will open new avenues for the treatment of bipolar disorder.

Bauer oversaw the clinical trial and is the lead author of both journal articles.

The new model was developed and tested in veterans with bipolar disorder at the Providence V.A. Medical Center. During the trial, 306 veterans were enrolled at 11 V.A. centers located in Arizona, California, Colorado, Georgia, Indiana, Maryland, Ohio, Pennsylvania, Tennessee and Texas. Each veteran was randomly assigned to a study group. One group got usual care through their psychiatrist. The other group received treatment under the new model.

Developed by Bauer and colleagues, the model brings together psychiatrists and nurses as a team to treat the patients. Psychiatrists monitored symptoms and handled medications. Nurse care coordinators worked with veterans during group education sessions.

During the weekly group sessions, nurses discussed topics such as medication side effects and early warning signs for symptoms, which in bipolar disorder range from racing speech, bursts of optimism and impulsive behavior during manic episodes to fatigue, social withdrawal and suicidal thoughts during depressive episodes. During the sessions, patients discussed coping skills, got feedback from the group and created personal action plans.

The intervention was tested for three years. The results: Under the new model, patients saw a significant reduction in symptoms, including five fewer weeks experiencing mania during the three-year study period. Patients also felt happier and healthier, reporting more productive time at work, better relationships with family, and more satisfaction with their care.

The new model was less expensive an average of $61,398 for three years of direct treatment costs compared with $64,379 for usual care although the difference was not statistically significant.

The bottom line is that we saw improvements in patients symptoms, function and quality of life with no change in net costs, Bauer said.

The results mirror those from a simultaneous trial testing a similar team-based approach for bipolar disorder that Bauer also helped to develop. That approach was tested in 441 patients enrolled in a Washington state health maintenance organization. Results from that trial were published in May in the Archives of General Psychiatry.

We now have results from more than 700 patients, cared for in very different health systems, that show this collaborative approach works, Bauer said. Just like anyone with a chronic illness, people with bipolar disorder can work with medical professionals to manage their symptoms and manage their lives.

Youth with bipolar disorder misread facial expressions as hostile

Tue, 30 May 2006 23:23:00 PST

( from http://www.rxpgnews.com ) Youth with bipolar disorder misread facial expressions as hostile and show heightened neural reactions when they focus on emotional aspects of neutral faces, researchers at the National Institutes of Health's (NIH) National Institute of Mental Health (NIMH) have discovered. The study provides some of the first clues to the underlying workings of the episodes of mania and depression that disrupt friendships, school, and family life in up to one percent of children.

Brain scans showed that the left amygdala, a fear hub, and related structures, activated more in youth with the disorder than in healthy youth when asked to rate the hostility of an emotionally neutral face, as opposed to a non-emotional feature, such as nose width. The more patients misinterpreted the faces as hostile, the more their amygdala flared. Such a face-processing deficit could help account for the poor social skills, aggression, and irritability that characterizes the disorder in children, suggest Drs. Ellen Leibenluft, Brendan Rich, Daniel Pine, NIMH Mood and Anxiety Disorders Program, and colleagues, who report on their findings May 29, 2006 in the Proceedings of the National Academy of Sciences.

"Since children seem to have a more severe form of the disorder, they may provide a clearer window into the underlying illness process than adult onset cases," explained Leibenluft. "Our results suggest that children with bipolar disorder see emotion where other people don't. Our results also suggest that bipolar disorder likely stems from impaired development of specific brain circuits, as is thought to occur in schizophrenia and other mental illnesses."

Magnetic Resonance Imaging (MRI) studies have shown that, unlike in adults with the illness, the amygdala is consistently smaller in bipolar children than in healthy age-mates. Also, the NIMH researchers had found earlier that bipolar children falter at identifying facial emotion and have difficulty regulating their attention when frustrated.

The left amygdala and related structures (yellow area where lines intersect) are part of an emotion-regulating brain circuit where children with bipolar disorder showed greater activation than controls when rating their fear of neutral faces. Structural MRI image with functional MRI data superimposed. Credit: Source: NIMH Mood and Anxiety Disorders Program

Using functional MRI, the researchers measured brain activity in 22 bipolar youth and 21 healthy subjects while they rated faces. In addition to the amygdala, other parts of the emotion-regulating circuit nucleus accumbens, putamen, and left prefrontal cortex were also hyperactive in patients, compared to healthy peers, during the emotional tasks. Patients rated themselves as more afraid, and they rated the faces as more hostile, compared to healthy peers. The groups did not differ on nose width ratings, confirming that the differences were specific to perceiving emotional processes.

"By finding a brain imaging trait that may be more selective than current clinical criteria, this line of research might help us refine our definition of pediatric bipolar disorder," said NIMH Director Thomas Insel, M.D. "The researchers are following-up with imaging studies of children with bipolar spectrum disorders and healthy children who are at genetic risk for developing the disorder to see if they also have the same amygdala over-activation."

Brain Changes Indicating Bipolar Disorder Are Not Prominent Until Adulthood

Tue, 31 Jan 2006 19:16:00 PST

( from http://www.rxpgnews.com ) Changes in the brain that are important indicators of bipolar disorder are not prominent until young adulthood and are reduced in persons taking mood-stabilizing medications, Yale School of Medicine researchers report this month in Biological Psychiatry.

The researchers used magnetic resonance imaging to measure a part of the brain that regulates emotions, the ventral prefrontal cortex, that lies above the eyes. The changes in persons with bipolar disorder were not prominent until young adulthood, suggesting that the illness progresses during the teenage years. Bipolar disorder is also known as manic-depressive illness.

"The brain changes were diminished in persons with bipolar disorder who were taking mood-stabilizing medications," said Hilary Blumberg, M.D., associate professor in the Department of Psychiatry and director of Yale's Mood Disorders Research Program. "This brings hope that it may someday be possible to halt the progression of the disorder."

Blumberg added, "Research to understand bipolar disorder in youths is especially important because of their high risk for suicide."

Bipolar disorder is characterized by episodes that range from emotional highs, or manias, to emotional lows, or depressions. Extreme manic highs can be associated with over-spending, impulsiveness on the job or at school, and risky behaviors, including sexual indiscretions that can lead to loss of important relationships. Blumberg said in depressive episodes individuals may "take to bed" or, in severe cases, try to take their own lives.

Manic-depressive illness and the FAT gene

Fri, 13 Jan 2006 20:26:00 PST

( from http://www.rxpgnews.com ) A collaboration, led by Sydney scientists at the Garvan Institute of Medical Research and University of New South Wales, has discovered the first risk gene specifically for bipolar disorder, also known as manic-depressive illness. This means that people who have a particular form of this gene are twice as likely to develop the disease.

Dr Ian Blair, lead author of the research paper published in Molecular Psychiatry, says: We are the first group in the world to take a multi-faceted approach to identify a bipolar risk gene - we used a number of families, unrelated patients, and therapeutic drug mouse models. Each of these three lines of investigation led us to a gene called FAT.

We know that the FAT gene codes for a protein that is involved in connecting brain cells together, what we need to do now is find out exactly how the it contributes to the increased risk of bipolar disorder, explains Dr Blair.

Bipolar disorder is a major psychiatric illness affecting around one person in every 50. Tragically, around one in six people suffering from the condition will commit suicide.

Mood-stabilising medications are typically prescribed to help control bipolar disorder. Lithium was the first mood-stabilising medication approved by the U.S. Food and Drug Administration (FDA) for treatment of mania. For decades it has been widely prescribed for the treatment bipolar disorder, yet no one knows for sure why it works.

Dr Blairs research has raised the possibility that lithium exerts its therapeutic affect by altering FAT gene expression, as well as the expression of genes encoding FATs protein partners.

Lithium has a number of severe side effects that include tremor and weight gain. Kidney dysfunction may develop in a small proportion of patients when it is administered for long periods of time.

Once we understand exactly what the FAT gene does, we will be able to develop better diagnostic tests for bipolar disorder. In the future, we hope our research will lead to new, targeted medicines specifically for bipolar disorder that dont have the unpleasant side effects that lithium has, says Dr Blair.

One in five teens needing inpatient psychiatric care may be manic-depressive

Wed, 28 Dec 2005 18:31:00 PST

( from http://www.rxpgnews.com ) Clinicians at Bradley Hospital, the nation's first psychiatric hospital for children and adolescents and one of the country's leading bipolar treatment centers, have found that bipolar disorder is more common than expected in teens in a psychiatric inpatient setting.

"In the past, mental health professionals thought that about one percent of teens was bipolar our research indicates that if a strict definition of the illness is applied, up to twenty percent of adolescents on psychiatric units may be manic-depressive," says lead author Jeffrey Hunt, MD, a child psychiatrist at Bradley Hospital and clinical assistant professor of psychiatry at Brown Medical School. The study appears in the December issue of the Journal of Child and Adolescent Psychopharmacology.

Bipolar disorder, also known as manic depression, is characterized by dramatic mood swings from overly "high" and/or irritable to sad and hopeless, and then back again. "There are often periods of normal mood in between, but there is always accompanying serious impairment in functioning," says Hunt.

This disorder was once believed to be rare in children and adolescents, but because of controversies surrounding diagnosis in juveniles, and because few large-scale studies have been conducted, prevalence rates of bipolar disorder in clinical and community samples of children and adolescents remain difficult to determine, the authors write.

The authors say that screening patients for manic symptoms upon admittance to a psychiatric unit can ultimately lead to better treatment overall. For example, many psychiatric patients first present with symptoms of depression, but depression can also be an indicator of bipolar disorder. The danger lies in the fact that the medication for treating depression can actually have an adverse effect on someone with manic-depression.

"This research is important because diagnosis of juvenile bipolar disorder is controversial impulsivity, irritability and hyperactivity commonly occur in adolescents in general. If these symptoms all present concurrently, the challenge is to determine whether they are symptoms of bipolar disorder, or are simply a normal part of teenage development," says Hunt.

The authors assessed a total of 391 consecutive admissions to the psychiatric inpatient unit at Bradley Hospital using a mania rating scale derived from a well-known research interview called the K-SADS (the Kiddie Schedule for Affective Disorders and Schizophrenia) as well as other history from both parents and adolescents. They found that manic symptoms such as severe irritability, impulsivity, depression, and hypersexuality are frequently found in hospitalized adolescents. Twenty percent of these patients were diagnosed with juvenile bipolar disorder when information from all sources was integrated with the scores from the K-SADS mania rating scale.

This study is the first to apply the K-SADS mania rating scale with patients "off the street" (i.e., not selected for the study). The authors screened all adolescent admissions to Bradley Hospital regardless if they had a history of mania. Prior research studies using this scale on bipolar prevalence rates only looked at previously diagnosed patients.

The authors found that, compared to patients admitted for depression alone, bipolar patients were more suicidal and aggressive, consequently needing higher levels of care. In addition, over half of the patients diagnosed with juvenile bipolar disorder were admitted during a depressive episode.

"So you might not be able to tease out the difference between a manic-depressive episode and depression unless you can accurately test for bipolar disorder," says Hunt. "We found that the K-SADS was an effective way to as accurately as possible diagnose bipolar disorder, and to help prevent treating bipolar patients presenting in a depressed phase with antidepressants," Hunt states.

According to the National Institute of Mental Health (NIMH), bipolar disorder typically develops in late adolescence or early adulthood. However, some people have their first symptoms during childhood, and some develop them late in life. It is often not recognized as an illness, and people may suffer for years before it is properly diagnosed and treated.

Psychosocial Disability Fluctuates Along with Bipolar Symptoms

Thu, 08 Dec 2005 15:24:00 PST

( from http://www.rxpgnews.com ) With every increase or decrease in depressive symptom severity, there is a corresponding significant and stepwise increase or decrease in psychosocial disability among patients with bipolar disorder, according to a study in the December issue of Archives of General Psychiatry, one of the JAMA/Archives journals.

Bipolar disorder is characterized by cycles of depression and abnormal elation, or mania. It has been found to be associated with increased suicidal behavior, increased health care use and costs, higher unemployment, higher dependence on public assistance, lower annual income, increased work absenteeism owing to illness, decreased work productivity, poorer overall functioning, lower quality of life, and decreased life span, according to background information in the article. Bipolar I disorder (BP-I), which includes episodes of mania, and bipolar II disorder (BP-II), which includes less severe episodes of abnormal mood elevation called hypomania, are dimensional illnesses in which patients experience fluctuating levels of severity of manic and depressive symptoms, interspersed with symptom-free periods.

Lewis L. Judd, M.D., of the University of California, San Diego, and colleagues conducted a study to provide detailed data on psychosocial disability in relation to symptom status during the long-term course of BP-I and BP-II. They analyzed data on 158 patients with BP-I and 133 patients with BP-II who were followed up for an average of 15 years in the National Institute of Mental Health Collaborative Depression Study.

The authors found that symptom severity and psychosocial disability fluctuate together during the course of illness.

Psychosocial impairment increases significantly with each increment in depressive symptom severity for BP-I and BP-II and with most increments in manic symptom severity for BP-I, they write.

When patients with BP-I or BP-II are asymptomatic, their psychosocial functioning is good, but not as good as that of well controls.

When patients with BP-I or BP-II have no mood disorder symptoms, their psychosocial functioning normalizes and is rated as good; when they are experiencing subsyndromal depression, psychosocial functioning is between good and fair; when minor depressive or dysthymic symptoms are present, functioning is fair; and when patients have symptoms at the threshold for major depression, functioning is poor, the authors write.

These findings indicate that the depressive phase of bipolar illness is equal in importance to the manic or hypomanic phase, and they confirm the advantage of studying BP-I and BP-II separately, the authors conclude.

BOLDER II (BipOLar DEpRession) study - Quetiapine effective in bipolar depression

Mon, 24 Oct 2005 13:57:00 PST

( from http://www.rxpgnews.com ) Newly released top-line results from the BOLDER II (BipOLar DEpRession) study have underlined the potential for SEROQUEL (quetiapine fumarate) in the treatment of patients with major depressive episodes associated with bipolar disorder. In BOLDER II, SEROQUEL 300mg and 600mg doses achieved a statistically significant reduction in levels of bipolar depression compared with placebo (p less than 0.001), as measured by the change from baseline in MADRS* total score.1

BOLDER II, an eight week, multi-centre, placebo-controlled study, reinforces the findings of the landmark BOLDER I study2 published in American Journal of Psychiatry in July 2005, which first indicated a significant effect for SEROQUEL in treating major depressive episodes associated with bipolar disorder.

In BOLDER II, the significant reduction in MADRS total score was seen both in patients with bipolar I and bipolar II disorder, in patients with or without a rapid cycling course of illness, and as early as week one after randomisation. Significant improvements were also seen compared with placebo in the various secondary study endpoints among SEROQUEL-treated patients, including reduction of anxiety symptoms. In addition, more than half (53%) of patients receiving SEROQUEL achieved remission** from their bipolar depression symptoms.

Importantly, SEROQUEL was shown to be well tolerated in BOLDER II with a similar safety profile seen to that in BOLDER I. The rate of serious adverse events was low and comparable in all treated groups. The most common adverse events reported in the trial were dry mouth, sedation, somnolence, dizziness and constipation, and there was a low incidence of treatment-emergent mania in the SEROQUEL-treated groups.

As in BOLDER I, there was a low incidence of EPS (extrapyramidal symptoms) and minimal weight change reported in the study.

* MADRS (Montgomery- Åsberg Depression Rating Scale) measures the severity of a number of depressive symptoms including mood and sadness, tension, sleep, appetite, energy, concentration, suicidal ideation and restlessness. The MADRS score decreases as depression symptoms improve.

** Remission defined as a score of less than 12 on the MADRS scale (Montgomery-Asberg Depression Rating Scale) at any point in time during the study

Professor Joseph Calabrese, co-director of the National Institute of Mental Health Bipolar Research Center at University Hospitals of Cleveland and Case Western Reserve University says: "Patients with bipolar depression are underserved and understudied. The findings from the BOLDER II study are very encouraging and support the findings of BOLDER I, in showing the potential of SEROQUEL, as monotherapy, for the acute treatment for bipolar depression. Each of these two studies represent the largest placebo-controlled short-term studies ever conducted in bipolar depression. The beneficial risk:benefit profile of Seroquel seen in both studies could offer an important therapeutic value for both patients and physicians as we currently have only one FDA-approved therapy to treat depressive episodes associated with bipolar disorder."

Bipolar disorder is a serious mental illness that affects approximately 3-4% of the adult population and is the sixth leading cause of disability in the world.3,4,5,6 Patients with bipolar disorder are symptomatic almost half of their lives, and approximately two-thirds of that time is spent in the depressed phase of the illness.7 Currently SEROQUEL is only approved for the treatment of mania associated with bipolar disorder.

"BOLDER II shows that SEROQUEL may provide substantial clinical benefits to patients with bipolar disorder", commented Carolyn Fitzsimons, Seroquel Commercial VP. "Based on prior discussions with the FDA and the results of BOLDER II, AstraZeneca plans to file for a US licence extension for SEROQUEL in the treatment of depressive episodes associated with bipolar disorder around the end of this year (2005)."

Call for accurate screening of bipolar disorder

Fri, 02 Sep 2005 02:09:00 PST

( from http://www.rxpgnews.com ) The British Journal of General Practice (BJGP) has published an editorial paper highlighting the vital role GPs play in distinguishing between unipolar and bipolar disorder and treating it accordingly.

Authors from the University of Melbourne, say there is increasing evidence that treating bipolar patients with unipolar therapy may be harmful to patients.

According to the authors, new research suggests that up to 30 per cent of patients presenting with depression in primary care are diagnosed with bipolar disorder. GPs are often the first clinicians to screen for bipolar disorder and manage its initial treatment. However, they say patients presenting with bipolar may be diagnosed with unipolar depression and as a result treated inaccurately, thereby potentially exacerbating the illness.

The authors conclude that GPs play a pivotal role in detecting, managing and, where necessary, appropriately referring patients with bipolar disorder. This role, they believe, is essential to the management of this highly prevalent and disabling, yet treatable, condition.

Dr Michael Berk, lead author and Professor of Psychiatry at the Department of Clinical and Biomedical Sciences, University of Melbourne, said: It is essential to accurately differentiate bipolar from unipolar depression as treatments are very different. Optimal outcomes are dependent on appropriate therapy. The key is to screen both for a past history of mania or hypomania and for the clinical signature of bipolar depression.

First study to test antipsychotic on depressive phase

Mon, 04 Jul 2005 13:50:00 PST

( from http://www.rxpgnews.com ) For the first time, researchers have demonstrated in separate short-term trials that a single drug therapy may be effective in treating both the manic and depressive phases of bipolar disorder. The condition (bipolar I and II) affects approximately 8 million Americans, who have relied on a combination of drugs to manage their symptoms, and who remain at high risk of committing suicide because of the difficulty in treating the disorder.

A study of the antipsychotic drug Seroquel is published in the July issue of the American Journal of Psychiatry. The study's principal investigator is Joseph R. Calabrese, MD, principal investigator and director of the National Institute of Mental Health (NIMH) Bipolar Research Center at University Hospitals of Cleveland and Case Western Reserve University School of Medicine.

Dr. Calabrese led the randomized trial of 542 patients with bipolar depression at 39 sites in the United States. Seroquel is currently approved for the short-term treatment of acute manic episodes in bipolar I disorder and the treatment of schizophrenia. This is the first study of Seroquel in patients with both bipolar I (defined as one fully manic episode with periods of major depression) and bipolar II (defined as periods of hypomania, or high levels of energy and impulsiveness alternating with episodes of major depression), in which researchers specifically studied the drug's impact on the depressive phase of the illness. Typically, antipsychotic medications are not used as specific treatments for bipolar depression.

"Though we will soon undertake an even larger trial, these preliminary findings should shape the standard of care for bipolar disorder going forward," says Dr. Calabrese, professor of psychiatry at Case and a nationally renowned researcher in bipolar disease. The Center, which he co-directs with pediatric psychiatrist Dr. Robert Findling, is the first NIMH-funded center exclusively dedicated to the development of new treatments for bipolar disorder.

"There was a dramatic response within eight days of beginning treatment in patients who were symptomatic with bipolar depression," says Dr. Calabrese. "About 50% of patients responded quickly to treatment with Seroquel versus placebo, achieving remission from their symptoms, with the response lasting through the eighth and last week of the trial. Seroquel was also twice as effective as placebo in decreasing suicidal thoughts associated with acute bipolar depression."

"Patients who respond most positively are probably those who also exhibit anxiety and agitation," adds Dr. Calabrese. "We are not certain as to the mechanism of action in the brain, however we know the drug impacts neurotransmitters dopamine and serotonin. The most common side effect is fatigue, so it may not be the best initial approach in patients who experience significant lethargy as a symptom of depression."

The trial tested two dose levels of Seroquel (quetiapine fumarate), 300 or 600mg/d, versus placebo. Of the 539 patients enrolled, 358 had bipolar I and 181 had bipolar II. Common side effects included dry mouth (43%), sedation (31%), sleepiness (26%), dizziness (20%) and constipation (11%). The research was supported by AstraZeneca Pharmaceuticals.

Research zeros in on bipolar disorder genes

Fri, 17 Jun 2005 03:39:00 PST

( from http://www.rxpgnews.com ) Despite an intensive effort, researchers have yet to identify the genes that cause bipolar disorder, yet the practical benefits of such a discovery could reap rich rewards for those suffering from the mental illness.

New research findings presented today at the Sixth International Conference on Bipolar Disorder suggest specific genetic linkages that are associated with the mental illness, bringing researchers much closer to finding the elusive gene or genes. Another study finds an association between an abnormal thyroid condition and bipolar disorder, pointing to the possibility that a simple blood test could help identify those at risk.

To further investigate more specific genetic linkages, Marion Leboyer, M.D., Ph.D., of the University of Paris Faculty of Medicine, studied 87 bipolar sibling pairs from 70 European families who were participants in the European Collaborative Study on Early Onset Bipolar Affective Disorder and identified eight regions of genetic linkages that, while not necessarily the sole or unique ones associated with this disease, zeroed in on what may be the specific genes that predispose individuals to early onset of this debilitating disease.

According to Dr. Leboyer, his studies of families with members who developed the illness as children or adolescents reduces those genetic and clinical variabilities that can complicate efforts to identify susceptibility genes. Finding these genes would help researchers develop more effective treatments or even prevent the disorder from occurring in at-risk individuals.

Other genetic clues come from results of two related studies involving adolescent and young adult offspring of bipolar parents and of twins with bipolar disorder, suggesting a genetic link between bipolar disorder and an abnormal thyroid condition.

Willem Nolen, M.D., Ph.D., of the University of Groningen Medical Centre, Netherlands, found that bipolar patients were twice as likely as healthy subjects to develop autoimmune thyroiditis (AT). Among the offspring of parents with bipolar disorder, who usually have an increased prevalence of bipolar and other mood disorders, there also was an increased prevalence of AT. Surprisingly, this finding did not seem to be related to whether their offspring themselves had been diagnosed with a psychiatric illness.

Among identical twins (who share all their genes) with at least one twin having bipolar disorder, prevalence of AT was increased in the other twin, irrespective of whether the other twin also had bipolar disorder. However among fraternal twins (who share 50 percent of their genes) with at least one fraternal twin having bipolar disorder, prevalence of AT was increased only in the other fraternal twin who also had bipolar disorder, but was not increased in the fraternal twin without the illness.

Dr. Nolen's research highlights the increasing importance of identifying endophenotypes clinical information unique to certain groups of individuals that may be predictive of risk for disease and course of illness. Although associated genes for bipolar disorder and AT have yet to be identified, AT may be an endophenotype for bipolar disorder. As such, the findings suggest that relatives of patients with bipolar disorder not only inherit the vulnerability for bipolar disorder and other mood disorders, but that some also may share the genetic vulnerability for developing AT.

If proven valid in further studies, the research suggests that members of families in which bipolar disorder occurs could be tested for autoimmune thyroiditis by means of a simple blood analysis, thereby helping to identify those who also may be at risk for developing bipolar disorder.

"Why hasn't a gene for bipolar disorder been identified when clearly the illness affects some families more than others and what is science telling us about who is most vulnerable and how the onset of the illness can be prevented? While a number of genes have been suspected to be associated with bipolar disorder, we thus far have failed to isolate any definitive bipolar gene, but are making sure progress that will ultimately bring answers about how and why this debilitating disease affects so many. By exploring these genetic connections, we inch closer to surer diagnosis and more rational and effective treatments," commented Michael Thase, M.D., professor of psychiatry at the University of Pittsburgh School of Medicine.

DNA microarrays used to detect Bipolar Genes

Thu, 24 Mar 2005 05:34:00 PST

( from http://www.rxpgnews.com ) While lithium treatment has proven to be a godsend for many of the two million Americans with bipolar disorder, it is not without its downside. People on the drug may develop hypothyroidism, tremors, cognitive impairment, and excessive thirst and urination and gain weight.

However, better treatments for bipolar disorder depend on a better understanding of the still-mysterious mechanism by which lithium damps the highs and lows of the disorder. Now, researchers led by Philip Brandish of Merck & Co., Inc., and Edward Scolnick of the Broad Institute (formerly of Merck and Co., Inc.) have identified genes whose activity appears to be switched on by lithium, suggesting more direct targets for drugs to treat the disorder.

Lithium is known to inhibit the production of an important cellular switch, called inositol monophosphate, so the researchers set out to find genes that were activated by this inhibition. They treated slices of rat brain with lithium chloride as well as a chemical that depletes inositol. The also treated other slices with the two chemicals, but added inositol.

The researchers used DNA microarrays--so-called "gene chips"--to detect genes that were unequivocally activated when inositol was depleted in the brain slices.

They discovered several genes that they concluded "suggest new directions toward the treatment of bipolar disorder."

The behavior of one such activated gene, called GPR88, has been found to be associated with a rat model of mania, they said. This gene codes for a protein that is an "orphan receptor"--that is, its cellular function in sensing external chemical signals is unknown.

The researchers also found that the gene called AD-CYAP1 was upregulated in the treated brain slices. This gene codes for a signaling molecule called PACAP in the brain and is known to be close to a chromosomal region that genetic studies have shown to be associated with a higher risk of bipolar disorder.

PACAP protein is found throughout the central nervous system, said the researchers. They cited studies demonstrating that mice in which the gene is knocked out show hyperactivity and defects in their circadian (day-night) behavior--both also characteristic of humans with bipolar disorder. Also, in animals, lithium has been shown to affect such circadian behavior. The protein also has been found to affect the activity of a key neurotransmitter, dopamine, in the brain, said the researchers. What's more, they found two other genes--PAM and GCH--that are involved in producing PACAP to be upregulated in the treated brain tissue.

Brandish and his colleagues said that such findings "suggest a coordinated upregulation of genes leading to increased dopamine signaling. In the light of the recent clinical data and human genetic linkage, it is tempting to speculate that PACAP night be a therapeutic effector of lithium in bipolar disorder."

They concluded that "the data presented here warrant further investigation of PACAP signaling in the brain and of the orphan receptor GPR88 as potential new targets in bipolar disorder."

FDA Approves Aripiprazole for Maintaining Efficacy in Bipolar I Disorder

Mon, 14 Mar 2005 08:50:00 PST

( from http://www.rxpgnews.com ) Bristol-Myers Squibb Company and Otsuka Pharmaceutical Co., Ltd. announced that the U.S. Food and Drug Administration (FDA) approved ABILIFY® (aripiprazole) Tablets and Oral Solution for maintaining efficacy in patients with Bipolar I Disorder with a recent manic or mixed episode who had been stabilized and then maintained for at least six weeks.

The FDA approved aripiprazole for the treatment of acute bipolar mania, including manic and mixed episodes associated with bipolar disorder, on September 29, 2004.

Clinical data demonstrated that patients who had been stabilized on aripiprazole for at least six weeks experienced a significant delay in time to relapse, the primary outcome measure for this study, as compared with those randomized to placebo .

The majority of these relapses were due to manic rather than depressive symptoms. There is insufficient data to know whether aripiprazole is effective in delaying the time to occurrence of depression in patients with Bipolar I Disorder. Physicians who elect to use aripiprazole for extended periods, that is, longer than six weeks, should periodically re- evaluate the long-term usefulness of the drug for the individual patient.

"This approval of aripiprazole is important news for patients who suffer from Bipolar I Disorder with manic and mixed episodes, as relapse is unfortunately, very common," said John Zajecka, M.D., Director, Treatment Research Center, and Associate Professor of Psychiatry, Rush University Medical Center. "As a physician, it is very encouraging to know that patients can benefit from aripiprazole throughout the different phases of their treatment."

The latest FDA approval is based on the positive results of a randomized, double-blind, multicenter, placebo-controlled trial designed to compare the maintenance of efficacy of aripiprazole versus placebo, measured by time to relapse. In this study, patients who had recently experienced a manic or mixed episode were first stabilized with aripiprazole for at least six consecutive weeks.

After meeting the stabilization criteria [Young Mania Rating Scale Total Score (Y-MRS) less than or equal to 10 and Montgomery-Asberg Depression Rating Scale (MADRS) less than or equal to 13 during four consecutive visits over a minimum of six weeks], 161 patients were given aripiprazole or placebo in the double-blind, randomization phase .

The primary endpoint was time to relapse of manic and depressive symptoms. Of those patients who experienced a relapse, patients treated with aripiprazole relapsed significantly later than placebo-treated patients (p-value equals 0.020) .

In addition, the total number of relapses was significantly fewer in patients treated with aripiprazole than with placebo (25 percent versus 43 percent, respectively; p-value equals 0.013) . The majority of these relapses were due to manic rather than depressive symptoms.

There is insufficient data to know whether aripiprazole is effective in delaying the time to occurrence of depression in patients with Bipolar I Disorder. The adverse events reported during this trial were generally consistent with those reported in other long-term placebo-controlled trials of aripiprazole.

"Bristol-Myers Squibb is pleased that aripiprazole received this important new treatment indication, now providing one medication that can help physicians and patients manage the illness," said Anthony Hooper, president, U.S. Pharmaceuticals, Bristol-Myers Squibb. "Our company is committed to providing important new treatment options for the millions of people suffering from mental illness and addressing the needs of their healthcare providers and families."

"We are extremely pleased that aripiprazole, the first and only available dopamine partial agonist, has reached another important milestone in the treatment of mental illness," said Tatsuo Higuchi, president and representative director, Otsuka Pharmaceutical Co., Ltd. "With this new indication, patients who have had success with aripiprazole during a manic or mixed phase can safely and effectively address their continuing therapy needs."

Aripiprazole is indicated for the treatment of schizophrenia, acute manic and mixed episodes associated with bipolar disorder, and now for maintaining efficacy in patients with Bipolar I Disorder with a recent manic or mixed episode who had been stabilized and then maintained for at least six weeks. Since its initial approval in 2002, over 3.7 million prescriptions have been written in the United States .

Aripiprazole is available by prescription only. In addition to administration as a once-daily oral tablet, aripiprazole was recently FDA-approved in an oral solution formulation. Now available in U.S. pharmacies, aripiprazole Oral Solution is an important new treatment option for adult patients who are unable to or have difficulty swallowing tablets, and provides flexibility in addressing individual patient needs. Patients should talk to their healthcare provider for more information. To learn more about aripiprazole and for full product information, please visit the related link.

As with all antipsychotic medications, including aripiprazole, a rare condition referred to as neuroleptic malignant syndrome (NMS) has been reported. As with all antipsychotic medications, prescribing should be consistent with the need to minimize the risk of tardive dyskinesia (TD).

Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, have been reported at an increased incidence in clinical trials of elderly patients with dementia-related psychosis treated with aripiprazole, including a significant dose response relationship in a fixed dose trial.

Aripiprazole is not approved for the treatment of patients with dementia-related psychosis.

Hyperglycemia, including some serious cases ranging from ketoacidosis, hyperosmolar coma, or death, has been reported in patients treated with atypical antipsychotics. Aripiprazole was not included in epidemiologic studies suggesting this risk; therefore the risk of hyperglycemia with aripiprazole is not known. However, there have been few reports of hyperglycemia in patients treated with aripiprazole. Patients should be appropriately tested before and monitored during treatment.

Aripiprazole may be associated with orthostatic hypotension and should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or conditions which would predispose them to hypotension.

As with other antipsychotic drugs, aripiprazole should be used with caution in patients with a history of seizures or with conditions that lower the seizure threshold. Seizures occurred in 0.3% of bipolar patients treated with aripiprazole in placebo-controlled trials.

Like other antipsychotics, aripiprazole may have the potential to impair judgment, thinking or motor skills. Patients should not drive or operate hazardous machinery until they are certain aripiprazole does not affect them adversely.

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotics. Appropriate care is advised for patients who may exercise strenuously, be exposed to extreme heat, receive concomitant medications with anticholinergic activity, or be subject to dehydration.

As antipsychotics have been associated with esophageal dysmotility and aspiration, aripiprazole should be used cautiously in patients at risk for aspiration pneumonia.

As the possibility of a suicide attempt is inherent in psychotic illness and bipolar disorder, close supervision of high-risk patients should accompany drug therapy.

Physicians should determine if a patient is pregnant or intends to become pregnant while taking aripiprazole. Patients should be advised not to drink alcohol, or breast-feed while taking aripiprazole.

Both CYP3A4 and CYP2D6 are responsible for aripiprazole metabolism. Agents that induce CYP3A4 (e.g., carbamazepine) could cause an increase in aripiprazole clearance and lower blood levels. Inhibitors of CYP3A4 (e.g., ketoconazole) or CYP2D6 (e.g., quinidine, fluoxetine, or paroxetine) can inhibit aripiprazole elimination and cause increased blood levels.

Commonly observed adverse events reported with aripiprazole in 3-week bipolar mania trials at a greater than or equal to 5% incidence for aripiprazole and at a rate at least twice the rate of placebo include, respectively, akathisia (15% vs 4%), constipation (13% vs 6%), and accidental injury (6% vs 3%).

Treatment-emergent adverse events reported with aripiprazole in short-term trials at an incidence greater than or equal to 10% and greater than placebo, respectively, include:

-headache (31% vs 26%)
-agitation (25% vs 24%)
-anxiety (20% vs 17%)
-insomnia (20% vs 15%)
-nausea (16% vs 12%)
-dyspepsia (15% vs 13%)
-somnolence (12% vs 8%)
-akathisia (12% vs 5%)
-lightheadedness (11% vs 8%)
-vomiting (11% vs 6%) and
-constipation (11% vs 7%).

The adverse events reported in a 26-week, double-blind schizophrenia trial comparing aripiprazole and placebo were generally consistent with those reported in the short-term, placebo-controlled schizophrenia trials, except for a higher incidence of tremor: 9% for aripiprazole vs 1% for placebo. In addition, in a long-term (52-week), active-controlled study, the incidence of tremor for aripiprazole was 4%.

Aripiprazole is taken once daily with or without food.

Half of people with Bipolar Disorder experienced abuse in childhood

Thu, 10 Feb 2005 17:51:00 PST

( from http://www.rxpgnews.com ) Severe childhood trauma appears to have occurred in about half of people with bipolar disorder, according to a new study from the USA published in the February 2005 issue of the British Journal of Psychiatry.

Childhood abuse has been associated with many different types of adult psychiatric disorder, including suicidality, substance misuse and dependence, and psychosis. This study set out to examine the prevalence and types of childhood abuse reported by adult patients with bipolar disorder, and to relate them to the complexity of the current illness.

100 patients were studied at an academic specialty centre for the treatment of bipolar disorder in New York. Histories of severe childhood abuse were identified in about half of the sample and were associated with onset of illness at an early age, as well as with more severe manic symptoms, compared with patients without a history of abuse.

Severe emotional abuse or neglect was significantly associated with substance misuse or dependence. Rapid cycling between manic and depressive mood in the last year was significantly linked to severe emotional abuse or neglect, or physical abuse.

There was also a significant association between a lifetime suicide attempt and severe childhood sexual abuse (though not emotional or physical abuse).

Multiple forms of abuse in childhood - which occurred in about a third of the people studied - showed a graded increase in risk for both suicide attempts and rapid recycling between manic and depressive mood in adulthood.

The prevalence of severe childhood abuse found in around half of the sample is consistent with the findings of previous studies, and is only slightly higher than that found among patients with major depression.

Also consistent with the findings of this study are reports suggesting that multiple forms of child maltreatment often occur together, and may contribute additively or synergistically to psychiatric disorders and suicidality seen in adulthood.

The authors of the study comment that in the light of the high prevalence of childhood abuse in their sample, coupled with its influence on suicide risk, it would seem prudent for clinicians routinely to evaluate histories of childhood trauma in patients with bipolar disorder.

Consideration of the nature and extent of abuse in childhood may also bear directly on suicide risk assessment among these patients.

Further prospective studies are needed to confirm and extend the findings of this study.